scholarly journals Inhibitory effects of α-Mangostin on T cell cytokine secretion via ORAI1 calcium channel and K+ channels inhibition

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10973
Author(s):  
Hyun Jong Kim ◽  
Seorin Park ◽  
Hui Young Shin ◽  
Yu Ran Nam ◽  
Phan Thi Lam Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ion Channels ◽  
Calcium Channel ◽  
Immune Cells ◽  
Potassium Ion ◽  
Cytokine Secretion ◽  
Potassium Ion Channels ◽  
Dependent Manner ◽  
Anti Inflammatory

Background As one of the main components of mangosteen (Garcinia mangostana), a tropical fruit, α-mangostin has been reported to have numerous pharmacological benefits such as anti-cancer, anti-inflammatory, and anti-allergic effects through various mechanisms of action. The effects of α-mangostin on intracellular signaling proteins is well studied, but the effects of α-mangostin on ion channels and its physiological effects in immune cells are unknown. Generation of intracellular calcium signaling is a fundamental step for T cell receptor stimulation. This signaling is mediated not only by the ORAI1 calcium channel, but also by potassium ion channels, which provide the electrical driving forces for generating sufficient calcium ion influx. This study investigated whether α-mangosteen suppress T cell stimulation by inhibiting ORAI1 and two kinds of potassium channels (Kv1.3 and KCa3.1), which are normally expressed in human T cells. Methods This study analyzed the inhibitory effect of α-mangostin on immune cell activity via inhibition of calcium and potassium ion channels expressed in immune cells. Results α-mangostin inhibited ORAI1 in a concentration-dependent manner, and the IC50 value was 1.27 ± 1.144 µM. Kv1.3 was suppressed by 41.38 ± 6.191% at 3 µM, and KCa3.1 was suppressed by 51.16 ± 5.385% at 3 µM. To measure the inhibition of cytokine secretion by immune cells, Jurkat T cells were stimulated to induce IL-2 secretion, and α-mangostin was found to inhibit it. This study demonstrated the anti-inflammatory effect of α-mangostin, the main component of mangosteen, through the regulation of calcium signals.

scholarly journals 720 Targeting MARCO and IL-37R on anti-inflammatory macrophages in lung cancer blocks regulatory T cells and shift balance to support cytotoxic lymphocyte function

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A762-A762
Author(s):  
Linnéa La Fleur ◽  
Johan Botling ◽  
Fei He ◽  
Catarina Pelicano ◽  
Giorgia Palano ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Immune Suppression ◽  
Immune Cells ◽  
Cytotoxic T Cell ◽  
Lymphocyte Function ◽  
Anti Inflammatory

BackgroundThe progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment (TME). In non-small cell lung cancer (NSCLC) accumulation of anti-inflammatory tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Numerous clinical trials aiming to recover T cell anti-tumor activity have been failing due to the persistence immune suppression in TME. Thus, there is a clinical need for alternative treatments targeting the suppressive function of the TME. We have previously shown that antibodies targeting the scavenger receptor MARCO reprograms the pro-tumoral TAMs in murine cancer models. Here, we investigated the immune landscape of NSCLC in the presence of MARCO expressing TAMs. We tested targeting MARCO or the tumor mechanisms inducing MARCO on human TAMs and hypothesized that targeting these mechanisms will remodel the suppressive environment and relive the anti-tumor responses to increase the efficacy of immunotherapy.MethodsTo test our hypothesis, we first investigated the immune landscape of NSCLC in the presence of pro-tumoral MARCO+TAMs compared with tumors infiltrated by MARCO-TAMs. We next used RNAseq to analyze differential gene expression in NSCLC tumors infiltrated by MARCO positive or negative macrophages. In vitro, cytokine differentiated macrophages alternatively cultured with lung cancer cell lines were co-cultured with Natural Killer (NK) cells and T cells to mimic their interaction in the TME. Later, macrophages were treated with targeting antibodies and their phenotype and function were examined prior and following interaction with other immune cells.ResultsWe found that MARCO expressing TAM numbers correlated with increased occurrence of regulatory T cell and effector T cells and decreased NK cells in NSCLC infiltrated by MARCO+TAMs. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. Studies in vitro subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an anti-inflammatory phenotype through the release of IL-37. These human MARCO expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) repolarized TAMs resulted in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells.ConclusionsIn summary, our data demonstrate a novel immune therapeutic approach targeting human TAM immune suppression of NK and T cell anti-tumor activities and remodel immune suppression.Ethics ApprovalThe study was approved by Institutional Ethics Board, approval number Dnr 2013.977-31.1.

scholarly journals NKG2D receptor regulates human effector T-cell cytokine production

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6571-6581 ◽  
Author(s):  
Amorette Barber ◽  
Charles L. Sentman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Dependent Manner ◽  
Effector T Cell ◽  
Anti Inflammatory ◽  
Nkg2d Receptor ◽  
Cell Cytokine Production

Abstract Although innate immune signals shape the activation of naive T cells, it is unclear how innate signals influence effector T-cell function. This study determined the effects of stimulating the NKG2D receptor in conjunction with the TCR on human effector CD8+ T cells. Stimulation of CD8+ T cells through CD3 and NKG2D simultaneously or through a chimeric NKG2D receptor, which consists of NKG2D fused to the intracellular region of CD3ζ, activated β-catenin and increased expression of β-catenin–induced genes, whereas T cells stimulated through the TCR or a combination of the TCR and CD28 did not. Activation by TCR and NKG2D prevented expression and production of anti-inflammatory cytokines IL-10, IL-9, IL-13, and VEGF-α in a β-catenin– and PPARγ- dependent manner. NKG2D stimulation also modulated the cytokine secretion of T cells activated simultaneously through CD3 and CD28. These data indicate that activating CD8+ T cells through the NKG2D receptor along with the TCR modulates signal transduction and the production of anti-inflammatory cytokines. Thus, human effector T cells alter their function depending on which innate receptors are engaged in conjunction with the TCR complex.

Abstract 586: CD40L on T Cells is a Major Contributor to Atherosclerosis in Hyperlipidemic Mice

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Norbert Gerdes ◽  
Christina Buerger ◽  
Holger Winkels ◽  
Christian Weber ◽  
Esther Lutgens
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Chronic Inflammatory Disease ◽  
Chow Diet ◽  
Gene Markers ◽  
Anti Inflammatory

Atherosclerosis is a lipid driven chronic inflammatory disease of the arterial wall, involving both innate and adaptive immune responses. Specialized immune cells such as monocytes, B cells, T cells and dendritic cells (DCs) contribute to disease progression or control the inflammatory responses. The CD40-CD40L dyad was identified as an efficient modulator of cellular immune responses. CD40 is a member of the tumor necrosis factor receptor (TNFR) superfamily and is activated by CD40 ligand (CD40L). CD40 and CD40L both are expressed on the majority of immune and non-immune cells associated with atherosclerosis. However, the specific contribution of CD40-CD40L signaling on the different single cell types towards atherosclerosis progression remains undefined. Here, we aimed to investigate the cell type-specific mechanisms of CD40-CD40L interactions in atherosclerosis by generating mice with a conditional ablation of CD40L on T cells. Hyperlipidemic mice with a T cell-specific deficiency of CD40L developed significantly smaller atherosclerotic lesions in the ascending after 28 weeks of chow diet, and following 6 weeks of a cholesterol-enriched diet when compared to their littermate controls. Changes in lesion size were accompanied by a modified anti-inflammatory plaque phenotype, characterized by an increased proportion of smooth muscle cells and a reduced number of pro-inflammatory immune cells, such as macrophages and T cells. T cell CD40L-deficient mice displayed systematically reduced expression of pro-inflammatory cytokines such as IL-1β, IL-2, IL-12, and IFNγ, and increased expression of anti-inflammatory cytokines IL-10 and TGFβ. This anti-inflammatory milieu was paralleled a change in the development and activation status of the T cells with mice lacking CD40L on T cells displaying a reduction in the expression of cytokines and gene markers associated with the activation of T cells (e.g., IL-2, CD69). This change was also reflected within the T cell populations which had a reduced proportion of activated effector T cells and an increased ratio of naïve T cells. Thus, our study ascribes CD40L on T cells a central role in atherosclerosis.

scholarly journals Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses

2020 ◽  
Vol 4 (10) ◽  
pp. 2143-2157 ◽  
Author(s):  
Alak Manna ◽  
Timothy Kellett ◽  
Sonikpreet Aulakh ◽  
Laura J. Lewis-Tuffin ◽  
Navnita Dutta ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Lymphocytic Leukemia ◽  
Dependent Manner

Abstract Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL–patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.

scholarly journals The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tian-Yu Lei ◽  
Ying-Ze Ye ◽  
Xi-Qun Zhu ◽  
Daniel Smerin ◽  
Li-Juan Gu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Ischaemic Stroke ◽  
Immune Cells ◽  
Tissue Injury ◽  
Recovery Period ◽  
Vital Functions ◽  
Anti Inflammatory

AbstractThrough considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

scholarly journals Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rhianna Jones ◽  
Kyle Kroll ◽  
Courtney Broedlow ◽  
Luca Schifanella ◽  
Scott Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Rhesus Macaques ◽  
Oral Microbiome ◽  
Probiotic Supplementation ◽  
Siv Infection ◽  
Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

scholarly journals Innate Immune Cells and Their Contribution to T-Cell-Based Immunotherapy

2020 ◽  
Vol 21 (12) ◽  
pp. 4441 ◽  
Author(s):  
Pierpaolo Ginefra ◽  
Girieca Lorusso ◽  
Nicola Vannini
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cells ◽  
Adoptive Cell Therapy ◽  
Adaptive Immune Response ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Innate Immune Cells

In recent years, immunotherapy has become the most promising therapy for a variety of cancer types. The development of immune checkpoint blockade (ICB) therapies, the adoptive transfer of tumor-specific T cells (adoptive cell therapy (ACT)) or the generation of T cells engineered with chimeric antigen receptors (CAR) have been successfully applied to elicit durable immunological responses in cancer patients. However, not all the patients respond to these therapies, leaving a consistent gap of therapeutic improvement that still needs to be filled. The innate immune components of the tumor microenvironment play a pivotal role in the activation and modulation of the adaptive immune response against the tumor. Indeed, several efforts are made to develop strategies aimed to harness innate immune cells in the context of cancer immunotherapy. In this review, we describe the contribution of innate immune cells in T-cell-based cancer immunotherapy and the therapeutic approaches implemented to broaden the efficacy of these therapies in cancer patients.

600 In vitro anticancer and immunomodulatory activities of NBT-167, a dimer of resveratrol

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A635-A635
Author(s):  
Jeffrey Zhang ◽  
Everett Henry ◽  
L Harris Zhang ◽  
Wanying Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Immune Cells ◽  
Cell Killing ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Raw264.7 Macrophages

BackgroundResveratrol (3,4’,5-trihydroxystilbene), a stilbenoid isolated from many species of plants, is widely known for its antioxidative, anti-inflammatory, immunomodulatory and anticancer activities. Recently, novel resveratrol oligomers have been isolated from various plants; their diverse structures are characterized by the polymerization of two or more resveratrol units. Little is known regarding the anticancer and immunomodulating activities of these oligomers. In this study, we designed in vitro models to compare resveratrol side by side with its natural dimer NBT-167 for their anticancer and immunological activities.MethodsWe isolated resveratrol and its dimer (NBT-167) from plants. The potency of the compounds was compared side by side using cancer cell survival assays and immunological assays with various types of human cells including cancer cell lines, PBMCs and enriched NK, gamma delta T cells, THP-1 monocytic cells, HL-60 promyelocytic leukemia cells as well as mouse RAW264.7 macrophages.ResultsNBT-167 was found to be more potent than resveratrol in inhibiting growth of various cancer cells and modulation of cytokine production from anti-IgM, LPS, PHA or SEB stimulated PBMC. Both compounds similarly enhanced IL-2 stimulated NK and gamma delta T cell killing activity against K562 cells and modulated nitric oxide production from LPS/IFN-g induced RAW264.7 macrophages and phagocytotic activity of HL-60 cells. NBT-167 was slightly more potently than resveratrol in inhibiting chemotaxis of HL-60 cells and blocking cell cycle of THP-1 and HL-60 cells at G1/S transition. In addition, NBT-167, but not resveratrol, could increase IL-2 production and T cell proliferation stimulated with anti-CD3 and anti-CD28 and synergize with anti-PD-1 antibody to increase IL-2 and IFN-gamma production in co-culture of allotypic T cells and dendric cells (MLR).ConclusionsOur data showed that NBT-167, a dimer of resveratrol, had anticancer and immunomodulatory activities such as modulation of expression of cytokines in immune cells and induction of cancer cell-killing activities of NK and gamma delta T cells. Generally, NBT-167 appeared to have higher activities than resveratrol in modulating immune cells and inhibiting cancer cells. NBT-167 could be a promising cancer immunotherapeutic agent targeting both cancer cells and immune cells.

scholarly journals Direct and Indirect endocrine-mediated suppression of human endometrial CD8+T cell cytotoxicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Z. Shen ◽  
M. Rodriguez-Garcia ◽  
M. V. Patel ◽  
C. R. Wira
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cytotoxic Activity ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cd8 T Cell ◽  
Gynecological Cancers ◽  
Protective Strategies ◽  
T Cell Cytotoxicity

AbstractRegulation of endometrial (EM) CD8+T cells is essential for successful reproduction and protection against pathogens. Suppression of CD8+T cells is necessary for a tolerogenic environment that promotes implantation and pregnancy. However, the mechanisms regulating this process remain unclear. Sex hormones are known to control immune responses directly on immune cells and indirectly through the tissue environment. When the actions of estradiol (E2), progesterone (P) and TGFβ on EM CD8+T cells were evaluated, cytotoxic activity, perforin and granzymes were directly suppressed by E2 and TGFβ but not P. Moreover, incubation of polarized EM epithelial cells with P, but not E2, increased TGFβ secretion. These findings suggest that E2 acts directly on CD8+T cell to suppress cytotoxic activity while P acts indirectly through induction of TGFβ production. Understanding the mechanisms involved in regulating endometrial CD8+T cells is essential for optimizing reproductive success and developing protective strategies against genital infections and gynecological cancers.

Interferon-γ-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2570-2577 ◽  
Author(s):  
John Stagg ◽  
Sandra Pommey ◽  
Nicoletta Eliopoulos ◽  
Jacques Galipeau
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Stromal Cells ◽  
Matrix Protein ◽  
Marrow Stromal Cells ◽  
Human Mscs ◽  
Dependent Manner ◽  
Antigen Presenting ◽  
Significant Production

AbstractSeveral studies have demonstrated that marrow stromal cells (MSCs) can suppress allogeneic T-cell responses. However, the effect of MSCs on syngeneic immune responses has been largely overlooked. We describe here that primary MSCs derived from C57BL/6 mice behave as conditional antigen-presenting cells (APCs) and can induce antigen-specific protective immunity. Interferon gamma (IFNγ)-treated C57BL/6 MSCs, but not unstimulated MSCs, cocultured with ovalbumin-specific major histocompatibility (MHC) class II-restricted hybridomas in the presence of soluble ovalbumin-induced significant production of interleukin-2 (IL-2) in an antigen dose-dependent manner (P < .005). IFNγ-treated MSCs could further activate in vitro ovalbumin-specific primary transgenic CD4+ T cells. C57BL/6 MSCs, however, were unable to induce antigen cross-presentation via the MHC class I pathway. When syngeneic mice were immunized intraperitoneally with ovalbumin-pulsed IFNγ-treated MSCs, they developed antigen-specific cytotoxic CD8+ T cells and became fully protected (10 of 10 mice) against ovalbumin-expressing E.G7 tumors. Human MSCs were also studied for antigen-presenting functions. IFNγ-treated DR1-positive human MSCs, but not unstimulated human MSCs, induced significant production of IL-2 when cocultured with DR1-restricted influenza-specific humanized T-cell hybridomas in the presence of purified influenza matrix protein 1. Taken together, our data strongly suggest that MSCs behave as conditional APCs in syngeneic immune responses. (Blood. 2006;107:2570-2577)

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